One prerequisite for mammalian reproduction is an effective reciprocal interaction between an implantation-competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The goal of this proposal is to better understand the mechanisms that direct uterine receptivity and nonreceptivity with the aim of improving female fertility. We will use conditionally gene-deleted mouse models to address the molecular basis of these events, since these models provide mechanistic information relevant to fertility in women. Human reproduction is complex and not very efficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation due to an inappropriate uterine milieu. Unwanted pregnancy loss causes psychological and economical stress to families, and is a challenging clinical problem. Based on our published and preliminary results, we hypothesize that homeobox-cytokine-Wnt signaling, involving Msx1, leukemia inhibitory factor (LIF) and Wnt5a, is critical for implantation. To address these questions, we will pursue the following specific aims in mice: (1) The first Specific Aim will test the hypothesis that Msx1 plays key roles in regulating various phases of uterine sensitivity to implantation by altering the luminal epithelial cell polarity and epithelial- mesenchymal interactions;(2) The second Specific Aim will test the hypothesis that Msx1 and LIF closely interact to direct various phases of uterine sensitivity;and (3) The third Specific Aim will test the hypothesis that overexpression of uterine Msx1 results in implantation failure, but extends the uterine preparedness to implantation. Our preliminary results with conditional deletion of uterine Msx1 and/or deletion of Lif hold great promise and have created a window of opportunity to generate molecular and genetic information on potential mechanisms by which the uterus becomes receptive or nonreceptive. This research is clinically relevant because Msx1 is downregulated in the human endometrium during the receptive phase (window of implantation).This simulates the situation in mice in which Msx1 is downregulated just prior to the initiation of implantation. The results derived from the proposed study using mouse models may help developing novel strategies to improve fertility in women.